Objective: To investigate the effect of M(5) muscarinic receptor subtype on the locomotor sensitization induced by heroin priming, and it's effect on the FosB expression in the nucleus accumbens (NAc) and the hippocampus in the heroin sensitized rats.
Methods: Locomotor activity was measured every 10 min for 1 h after subcutaneous injection of heroin. FosB expression was assayed by immunohistochemistry, and the antisense oligonucleotides (AS-ONs) targeting M(5) muscarinic receptor was transferred with the lipofectin.
Results: Microinjection of AS-ONs targeting M(5) muscarinic receptor in the ventral tegmental area (VTA) blocked the expression of behavioral sensitization induced by heroin priming in rats. Meanwhile, the expression of FosB-positive neurons in either the NAc or the dentate gyrus (DG) of the hippocampus increased in heroin-induced locomotor sensitized rats. The enhancement of FosB-positive neurons in the NAc or DG could be inhibited by microinjection of M(5) muscarinic receptor AS-ONs into the VTA before the heroin-induced locomotor sensitization was performed. In contrast, microinjection of M(5) muscarinic receptor sense oligonucleotide (S-ONs) into the VTA did not block the expression of behavioral sensitization or the expression of FosB in the NAc or DG in the heroin sensitized rats.
Conclusion: Blocking M(5) muscarinic receptor in the VTA inhibits the expression of heroin-induced locomotor sensitization, which is associated with the regulation of FosB expression in the NAc and hippocampus neurons. M(5) muscarinic receptor may be a useful pharmacological target for the treatment of heroin addiction.
目的: 探讨 M5 毒蕈碱受体亚型对海洛因诱导的大鼠行为敏化以及敏化后大脑伏隔核 (NAc) 和海马中FosB蛋白表达的影响。
方法: 建立海洛因诱导的大鼠行为敏化模型, 测定大鼠的自主活动量 (locomotor activity, LA), 观察 M5 毒蕈碱受体反义寡核苷酸 (M5AS-ONs) 对行为敏化表达的影响。 用免疫组化法测定大鼠NAc 及海马齿状回 (DG) FosB 蛋白表达。
结果: 海洛因处理组与盐水处理组相比, 大鼠在 1 小时内的 LA 显著增 加, 表明这些大鼠已稳定建立了海洛因诱导的敏化。 中脑腹侧被盖区 (VTA) 中注射 M5 AS-ONs 能抑制大鼠 海洛因行为敏化的表达。 海洛因诱导的行为敏化大鼠中NAc及 DG 中的 FosB 免疫反应阳性神经元的表达增加, 而在 VTA 内注射 M5 AS-ONs 能明显抑制 NAc 及 DG 中 FosB 阳性神经元表达的增加; 但 VTA 中注射有义寡核 苷酸 (M5S-ONs) 不能明显抑制大鼠行为敏化的表达, 也不能抑制海洛因敏化大鼠NAc 和DG 中 FosB 蛋白的 表达。
结论: 阻断 VTA 中 M5 毒蕈碱受体可抑制海洛因诱导的行为敏化的表达, 其机制可能和抑制大脑 NAc 和 DG 神经元中 FosB 蛋白的激活有关。 M5 毒蕈碱受体可作为改变海洛因行为学效应的有效药理学靶点之一。